Research Summary

The Molecular Toxicology and Informatics Group, headed by B. Alex Merrick, Ph.D., uses advanced technologies and computational approaches to relate chemicals to genes, genes to pathways, and pathways to disease. Development of toxicity signatures will further our understanding of disease processes and contribute to predictive models of toxicity and chemical prioritization.

Current Projects

Archival tissue gene expression – Studies are being conducted to evaluate new technologies (e.g., NextGen sequencing) for retrospectively interrogating changes in DNA sequence/methylation patterns and/or RNA expression, using fresh frozen and formalin-fixed, paraffin embedded tissues from animal studies that are stored in the National Toxicology Program (NTP) tissue archives.

Dose-response data analysis methods – Data normalization and statistical methods have been developed and are being used to classify compounds as active vs. inactive in quantitative high throughput screens (qHTS).

Drug Matrix – A Toxicogenomics and tissue library is being hosted by the NTP. Drug Matrix contains a graphic user interface for rapid scoring of genomic signatures of toxicity based on in vivo study data from male rates at multiple dose and exposure durations. ToxFx is an accompanying automated toxicogenomics data analysis application.

Toxicity signatures – Toxicogenomic data from in vitro and in vivo exposures are being used to derive patterns of gene expression for predicting disease (e.g., tumor formation) and target organ toxicity.

B. Alex Merrick, Ph.D. is a Molecular Toxicologist who joined the NTP Biomolecular Screening Branch (BSB) in 2010. Merrick leads the Branch's Molecular Toxicology and Informatics Group. His responsibilities include identifying key signaling pathways altered by environmental toxicants and participating in the Tox21 collaboration between the NTP, the NIH Chemical Genomics Center (NCGC), the Environmental Protection Agency's National Center for Computational Toxicology (NCCT) and the Food and Drug Administration (FDA). He is especially interested in performing molecular analysis in NTP archival tissues to discover gene expression and epigenetic signatures from chemical toxicology studies. Collaborative work with the Cellular and Molecular Pathology Branch aims to use NTP archival research to further pathological insight, better understand mechanisms of chemical toxicity and contribute to predictive models of toxicity and chemical prioritization as a complementary effort to the Tox21 high throughput screening program. In addition, NextGen sequencing pilot projects will help NTP better evaluate chemically exposed tissues for differential transcript profiles that include splice variants, low copy transcripts and non-coding mRNA's.

Before joining the Biomolecular Screening Branch, Merrick was head of the Proteomics Group within the Division of Intramural Research's (DIR) National Center for Toxicogenomics. His group performed protein and gene expression profiling of hepatoxic agents to identify mechanisms of liver injury, with special interest in p53 biology.

Merrick received his Ph.D. in 1984 at the University of Nebraska Medical Center in Omaha, performing post-doctoral work in the Biology Division at Oak Ridge National Laboratory. He headed the Hepatotoxicology section at the US EPA in Cincinnati, OH from 1985 to 1988 before joining NIEHS in 1989. He currently serves as an adjunct Associate Professor in the Department of Environmental and Molecular Toxicology at NC State University.